Can ongoing joint injury and osteoarthritis drive widespread musculoskeletal pain?

Clinical and physiological evidence

• Continuous peripheral driving forces: In osteoarthritic and structurally injured joints, degenerative and inflammatory alterations within tissues—such as cartilage, bone, synovium, and infrapatellar fat pads—interact with mechanical stress and elevated local inflammatory mediators (e.g., nerve growth factor, pro-inflammatory cytokines). This persistent microenvironment continuously drives and excites primary afferent nociceptors, preventing the normal resolution of pain thresholds.
• Transition to sensitized pain states: A persistent, repetitive nociceptive barrage acts as a critical initiator and driver of both peripheral and central sensitization.
  • At the peripheral level, ongoing input lowers nociceptor activation thresholds and increases basal firing rates.
  • Centrally, this sustained signaling triggers spinal hyperexcitability, synaptic wind-up, and altered supraspinal processing. Clinical observations show that mitigating this peripheral drive (e.g., via successful joint replacement surgery) can lead to a significant reduction in central sensitization markers.

Mechanistic explanations

• NMDA receptor activation and wind-up: Persistent C-fiber nociceptive input to the spinal dorsal horn triggers sustained depolarization, relieving the magnesium block of $N$-methyl-D-aspartate (NMDA) receptors. This initiates an activity-dependent increase in synaptic efficacy and excitability (synaptic "wind-up").
• Loss of spinal inhibitory control: Central sensitization progresses to a loss of gamma-aminobutyric acid (GABA)-ergic and glycinergic inhibitory control (disinhibition) in the spinal dorsal horn. This degradation of surround and segmental inhibition weakens the normal sensory gate, allowing spinal cord neurons to respond to inputs from much wider anatomical territories.
• Receptive field expansion: The loss of synaptic inhibition directly causes the expansion and blurring of neuronal receptive fields. Spinal dorsal horn neurons begin to show heterosynaptic facilitation, inappropriately recruiting low-threshold sensory fibers (such as mechanoreceptive $A\beta$ fibers).
• Spatial pain propagation: The expansion of these receptive fields reduces the spatial tuning and sensory resolution of pain pathways. Consequently, localized joint pain progresses to secondary hyperalgesia and a diffuse, widespread musculoskeletal pain experience that extends far beyond the margins of the original injured tissue.

Bottom line

Ongoing structural damage and joint pathology act as persistent peripheral drivers that initiate and maintain peripheral and central sensitization. Mechanistically, this sustained nociceptive input leads to spinal NMDA-mediated hyperexcitability and a loss of GABAergic/glycinergic inhibition. This disinhibition expands spinal neuronal receptive fields, transforming localized joint discomfort into diffuse, widespread musculoskeletal pain.